Many neurodegenerative disorders, such as Alzheimer disease (AD) and Front temporal lobar degeneration (FTLD), share a common pathogenic mechanism: the abnormal accumulation of tau protein, either due to a mutation that affects its clearance or due to other factors that retard the degradation of wild type tau. The Zoghbi lab has proposed that identifying genes and genes networks that control the level of tau will reveal potential therapeutic entry points for tau-driven dementias. To this end we performed forward genetic knock- down screens in both human cells and Drosophila harboring genes that express tau. This approach revealed that down regulation of Nuak1, an AMPK-related kinase, decreases tau levels in human cells and in fruit-flies, and suppresses neurodegeneration in tau-expressing Drosophila. Kinases are important to study because they are excellent pharmacologic targets, and Nuak1 stands out as a potential drug target. The overarching hypothesis of my proposal is to understand the mechanisms by which Nuak1 contributes to tau pathogenesis, which will lead to a better understanding of tauopathies and related neurodegenerative diseases. During the mentored phase of the award, I will determine the role of Nuak1 in tau pathogenesis through genetic interaction studies in mice as well as biochemical approaches. These studies will be performed in Dr. Huda Zoghbi's laboratory at Baylor College of Medicine. Dr. Zoghbi has a history of outstanding contributions to science as well as a longstanding commitment to the mentorship of young scientists. As an independent investigator, I will determine the physiological and functional interactions between Nuak1 and tau, investigate how this interaction regulates axonal branching, and how the deregulation of Nuak1-tau complex triggers pathological tau accumulation. Furthermore, I will identify the potential role of A on Nuak1 activation and the subsequent toxic accumulation of tau. The proposed studies will provide a platform for investigation of Nuak1 function and its relevance to neurodegenerative diseases characterized by the pathological accumulation of tau. Information gained from these studies might lead to the development of effective therapeutics for this subset of neurodegenerative diseases.